Development of an effective HIV vaccine is the long-term solution to control HIV/AIDS world-wide. The failure of adenovirus type 5 based HIV-1 vaccines in humans that was designed to elicit primarily antiviral T cells strongly suggests the need to develop novel vaccine approaches that generate high levels of antiviral T cells with improved function as well as protective antibody. Development of novel adjuvants is necessary to enhance the immunogenicity and efficacy of HIV vaccines. In this HIVRAD, we will use molecules that target mTOR (mammalian target of rapamycin) and CD40 pathways as novel adjuvants to elicit high levels of polyfunctional virus-specific CD8 T cells, CD4 T cells that are resistant to HIV infection and high avidity protective antibody that will lead to enhanced control of HIV infection. This PPG has two projects and two cores. Our project 1 will test the potential of CD40L expressed on the surface of virus-like particles as an adjuvant to enhance the immunogenicity and efficacy of DNA/MVA SIV vaccine. Our project 2 will test the safety, immunogenicity and efficacy of rapamycin (inhibitor of mTOR) as an adjuvant for DNA/MVA SIV vaccine. In addition, we will test for the effects of rapamycin on other replication defective and replication competent viral vectors. Finally, we will test the synergy between inhibiting mTOR and activating CD40 pathways for enhancing the immunogenicity and efficacy of DNA/MVA SIV vaccines. The macaque studies that will be conducted in projects 1 and 2 will be supported by a non-human primate core. An administrative core will provide coordination between projects 1 and 2, and core B, and help with data management and data analyses. RELEVANCE: WHO estimates that there are currently 32 million humans living with HIV/AIDS. Drugs and improved treatment regimens have successfully prolonged the lives of infected individuals in first world countries. However, these are not affordable for the vast majority of HIV-infected individuals. Even in developed nations these are limited by toxicity, affordability, the need for rigorous adherence to therapy and the emergence of drug resistant viruses. Thus, there is a great need to develop a safe and effective HIV vaccine that provides a low-cost, low toxicity solution to long-term control of viral replication - the main goal of this PPG. PROJECT 1: Title: CD40L-Adjuvanted Vaccines for HIV/AIDS Project Leader: AMARA, R PROJECT 1 DESCRIPTION (provided by applicant): The failure of Ad5 based HIV-1 vaccine in humans that is designed to elicit primarily antiviral T cells strongly suggests the need to develop novel vaccine approaches that generate high levels of anti-viral T cells with improved function as well as protective Ab. The goal of this project is to adjuvant the cellular and humoral immunity elicited by our DNA/MVA vaccine that has just entered phase II testing in humans in US. Specifically, we propose to target the CD40 pathway on dendritic cells (DC) and B cells using CD40L. Stimulation of CD40 on DC results in production of IFNa and IL-12 that are critical for generation of highly functional antiviral CD8 response. Activation of B cells through CD40 is necessary for germinal center formation where affinity maturation of B cells occurs leading to generation of high avidity Ab. Here, we will express CD40L on the surface of a SIV virus-like particle (CD40L-VLP). These CD40L-VLPs are potent activators of DC and B cells in vitro. In addition, they can be targeted to DC (through interaction between gpl20 on VLP and CD4 on DC) and allow presentation of Env in its native form that is critical for eliciting broadly cross-reactive neutralizing Ab. In specific aim 1, we will test the potential of CD40L-adjuvanted DNA/MVA SIV vaccine to enhance control of a pathogenic SIV challenge. In addition, we will test whether delivering DNA by electroporation enhances the immunogenicity of the adjuvanted and non-adjuvanted DN/VMVA vaccines. Recent studies from Dr. Rafi Ahmed's lab (PI of project 2) demonstrated that mTOR regulates memory T cell development and inhibition of this pathway following infection or vaccination using rapamycin enhances the magnitude and functional quality of antigen-specific CD8 T cells. Rapamycin has also been shown to down regulate expression of CCR5 on CD4 T cells that results in marked reduction of HIV replication. This could be an added advantage for HIV vaccines, because the vaccine-elicited CCR5' virus-specific CD4 T cells may not be infected by the virus. Essentially we may be reducing the frequency of potential virus target cells while preserving the much-needed CD4 T cell help following infection. In specific aim 2, we will test the synergy between inhibiting mTOR and activating CD40 pathways for adjuvanting the immunogenicity and efficacy of DNA/MVA vaccines. RELEVANCE: WHO estimates that there are currently 32 million humans living with HIV/AIDS. Drugs and improved treatment regimens have successfully prolonged the lives of infected individuals in first world countries. However, these are not affordable for the vast majority of HIV-infected individuals. Even in developed nations these are limited by toxicity, affordability, the need for rigorous adherence to therapy and the emergence of drug resistant viruses. Thus, there is a great need to develop a safe and effective HIV vaccine that provides a low-cost, low-toxicity solution to long-term control of viral replication - the main goal of this PPG.